Polymorphic forms and process

ABSTRACT

The invention relates to a process for the manufacture of enantiomerically enriched or pure compounds of formula I 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 6 , R 7  and Q are defined as in claim 1 as well as their crystalline forms for the treatment of proliferative diseases such as cancer.

The invention relates to a process for the manufacture ofenantiomerically enriched or pure compounds of formula I

wherein

-   R¹, R², R³ independently of one another is H, A, Aryl, Heteroaryl,    Hal, —(CY₂)_(n)—SA, —(CY₂)_(n)—SCF₃, —(CY₂)_(n)—SCN, —(CY₂)_(n)—CF₃,    —(CY₂)_(n)—OCF₃, R, Cycloalkyl, —SCH₃, —SCN, —CF₃, —OCF₃, —OA,    —(CY₂)_(n)—OH, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN, —(CY₂)_(n)-Hal,    —(CY₂)_(n)—NR₂, (CY₂)_(n)—OA, (CY₂)_(n)—OCOA, —SCF₃,    (CY₂)_(n)—CONR₂, —(CY₂)_(n)—NHCOA, —(CY₂)_(n)—NHSO₂A, SF₅, Si(CH₃)₃,    CO—(CY₂)_(n)—CH₃, —(CY₂)_(n)—N-Pyrolidon, (CH₂)_(n)NRCOOR, NRCOOR,    NCO, (CH₂)_(n)COOR, NCOOR, (CH₂)_(n)OH, NR(CH₂)_(n)NR₂, C(OH)R₂,    NR(CH₂)_(n)OR, NCOR, (CH₂)_(n)Aryl, (CH₂)_(n)Heteroaryl,    (CH₂)_(n)R¹, (CH₂)_(n)X(CH₂)_(n)Aryl, (CH₂)_(n)X(CH₂)_(n)Heteroaryl,    (CH₂)_(n)CONR₂, XCONR(CH₂)_(n)NR₂, N[(CH₂)_(n)XCOOR]CO(CH₂)_(n)Aryl,    N[(CH₂)_(n)XR]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)XR]CO(CH₂)_(n)XAryl,    N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Aryl, N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Aryl,    N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRAryl,    N[(CH₂)_(n)NR₂]SO₂(CH₂)_(n)Aryl,    N[(CH₂)_(n)XR]CO(CH₂)_(n)Heteroaryl,    N[(CH₂)_(n)XR]CO(CH₂)_(n)XHeteroaryl,    N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Heteroaryl,    N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Heteroaryl,    N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Heteroaryl,    N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRHeteroaryl and wherein, R¹ and R³    together also may be —N—C(CF₃)═N—, —N—CR═N— or —N—N═N— and wherein    non-adjacent groups CY₂ can be replaced by X-   Y is H, A, Hal, OR, E-R¹,-   E is —NR¹SO₂—, —NR¹CO—, NR¹CONR¹—, —NR¹COO—, —NR¹CS—, —NR¹CSNR¹—,    —NR¹COS—, NR¹CSO—, —NR¹CSS or —NR¹—-   A is Alkyl or Cycloalkyl, wherein one or more H-atoms can be    replaced by Hal,-   Hal is F, Cl, Br or I-   R is H or A, in the case of geminal groups R together also —(CH₂)₅—,    —(CH₂)₄— or —(CH₂)_(n)—X—(CH₂)_(n), or —(CH₂)_(n)-Z-(CH₂)_(n),-   X is O, S or NR¹,-   Q is CH₂-E-(CH₂)_(p)R¹,-   Z is CH₂, X, CHCONH₂, CH(CH₂)_(n)NR¹COOR¹, CHNR¹COOR¹, NCHO,    CHCON(R¹)₂, CH(CH₂)_(n)COOR¹, NCOOR¹, CH(CH₂)_(n)OH, N(CH₂)_(n)OH,    CHNH₂, CH(CH₂)_(n)NR¹ ₂, CH(CH₂)_(n)NR¹ ₂, C(OH)R¹, CHNCOR¹, NCOR¹,    N(CH₂)_(n)Aryl, N(CH₂)_(n)Heteroaryl, CHR¹, NR¹, CH(CH₂)_(n)Aryl,    CH(CH₂)_(n)Heteroaryl, CH(CH₂)_(n)R¹, N(CH₂)_(n)COOR¹,    CH(CH₂)_(n)X(CH₂)_(n)Aryl, CH(CH₂)_(n)X(CH₂)_(n)Heteroaryl,    N(CH₂)_(n)CON(R¹)₂, NSO₂R¹, CHSO₂N(R¹)₂, XCONR(CH₂)_(n)N(R¹)₂,    NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)XAryl, NSO₂(CH₂)_(n)Aryl,    NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)NR¹Aryl, NCO(CH₂)_(n)Heteroaryl,    NCO(CH₂)_(n)XHeteroaryl, NSO₂(CH₂)_(n)Heteroaryl,    NCO(CH₂)_(n)NR¹Heteroaryl, N(CH₂)_(n)NR₂CH, CHO(CH₂)_(n)N(R¹)₂,    CHX(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)NR₂,-   R⁶ is unsubstituted Aryl or Heteroaryl or Aryl or Heteroaryl which    is substituted in at least one position by Hal, NO₂, CN, OR, A,    —(CY₂)_(n)—OR, —OCOR, —(CY₂), —CO₂R, —(CY₂), —CN, —NCOR, —COR oder    —(CY₂), —NR₂ or by Aryl or Heteroaryl which also may be substituted    by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂, CF₃, OCF₃, OCH(CF₃)₂,-   R⁷ is (C═O)—R, (C═O)—NR₂, (C═O)—OR, H or A    and-   n is 0, 1, 2, 3, 4, 5, 6 or 7-   p is 0, 1, 2, 3, 4, or 5, preferred 1 or 2-   s is 0, 1, 2, 3 or 4, particularly 0    as well as their pharmaceutically acceptable derivatives, solvates,    tautomeres, salts and polymorphic forms.

Preferred compounds of formula I are those of formula I1

wherein R¹ to R⁶ and Q has the meaning given above.

The compounds of the present invention are used for the treatment andprophylaxis of diseases that are influenced by inhibition, regulationand/or modulation of the mitotic motor proteins, especially the mitoticmotor protein Eg5. These are predominantely all types of cancer andother neoplastic diseases.

Similar compounds to those obtained by the present invention are e.g.disclosed in WO 2005/063735.

The compounds of the formula I and salts thereof are obtained by thefollowing process, characterised in that

a compound of the formula A

in which R¹, R² and R³ have the meanings indicated above,is reacted with a compound of the formula B

in whichR⁶ has the meaning indicated above,andwith a compound of the formula C,

preferably in the presence of a suitable solvent, preferablyacetonitrile and a protonic acid or Lewis acid, such as, for example,trifluoroacetic acid, hexafluoroisopropanol, bismuth(II) chloride,ytterbium(II) triflate, scandium(III) triflate or cerium(IV) ammoniumnitrate, preferably trifluoroacetic acid,a radical other than H is optionally introduced by conventional methodsfor R⁷, and in that the resulting alkohol is transformed into a leavinggroup, such as mesyl, tosyl, benzolsulfonyl, trifluormethysulfonyl,nonafluorbutylsulfonyl, Cl, Br or I, preferably mesyl, and furthertransformed in the amino derivatives of formula I by reaction with asuitable group containing an NH moiety, such as NH³ or HN(R¹)₂. Theamino derivatives and preferably the compounds of formula I, wherein Qis CH₂NH₂, are then subjected to a de-racemization step and furthertransformation into the other compounds of formula I by knownprocedures, such as alkylation, or acylation.

Surprisingly, it has been found that a racemic or non enantiomericallypure compound of formula I, and especially a compound of formula I,wherein Q is CH₂NH₂, are forming complexes with enantiomerically puretartraic acid derivatives, preferably benzoyl tartraic acid andespecially (2R,3R)-(−)-Di-O-benzoyl tartaric acid, which crystallizewith high enantiomeric purity.

After separation of the crystalline phase from a suitable solvent,preferably polar protic solvents, such as alcohols, their mixtures oralcohol/water mixtures, the enantiomerically further enriched or purecompound of formula I can be obtained from the complex by reaction witha base, such as alkali hydroxide, preferably sodium hydroxide. Theenantiomerically enriched or pure compounds of formula I, wherein Q isother than CH₂NH₂ are then obtained by standard synthesis starting fromthe enriched or pure compounds of formula I, wherein Q is CH₂NH₂.

Thus, the invention relates preferably to a process for the manufactureof enantiomerically enriched or pure compounds of formula I, comprisingthe following steps:

a) a racemic or non enantiomerically pure compound of formula I isreacted with a enantiomerically pure tartraic acid derivative, in asuitable solvent, preferably anorganic solvent, such that a crystallinecomplex is formedb) the complex formed in step a) is isolated and treated with a base andoptionallyc) the enantiomerically further enriched or pure compound of formula Iwhrerein Q is CH₂NH₂ is transformed into the further compounds offormula I, wherein Q is other than CH₂NH₂ by standard procedures, thattransform the primary amino-group.

Standard procedures as defined under c) are e.g. alkylation, amidation,acylation hydroxylation. Preferably a standard procedure is the reactionwith carbonyldiimidazole and an amine such asN,N-Diethylethylenediamine.

Above and below, the radicals R, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, Y, Q, Z,m, p and s have the meanings indicated for the formula I, unlessexpressly indicated otherwise. If individual radicals occur a number oftimes within a compound, the radicals adopt the meanings indicated,independently of one another.

A denotes alkyl, is preferably unbranched (linear) or branched, and has1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 C atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6 Catoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl, trifluoromethyl, pentafluoroethylor 1,1,1-trifluoroethyl. A also denotes cycloalkyl.

Cycloalkyl preferably denotes cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, but in particular cyclopentyl.

R¹ preferably denotes A, CF₃, OCF₃, SA, SCN, CH₂CN, —OCOA, Hal, SCF₃,preferably also t-butyl, —CH(CH₃)CH₂CH₃, isopropyl, ethyl or methyl. Inparticular, R¹ denotes t-butyl, isopropyl, ethyl, CF₃, methyl, Br, Cl,SCF₃, CH(CH₃)CH₂CH₃, n-propyl, OCH₃, SCH₃, n-butyl, —SCN, CH₂CN. R¹particularly preferably denotes t-butyl, isopropyl, ethyl or CF₃.

R² preferably denotes H, Hal, A or OA, in particular Br, cyclopropyl,OCH₃. Particular preference is furthermore given to H or F.

R³ preferably denotes H or A, in particular H. R³ is preferably in the5-position. In particular, R³ denotes H or F.

If the radicals and indices, such as, for example, n, occur more thanonce, the radicals and indices may, independently of one another, adoptdifferent values.

R⁶ preferably denotes phenyl, 2-, 3- or 4-pyridyl, pyrimidyl, furyl orthienyl, each of which is unsubstituted or mono- or polysubstituted byHal, CN, NO₂, OH, CF₃, OCH(CF₃)₂, OCOCH₃ or A. R⁶ is preferably not aheteroaromatic radical. In particular, R⁶ denotes one of the followinggroups:

in which

-   X denotes O, S or NR and in particular O or S, A has the meaning    indicated above, but preferably denotes methyl, and Hal preferably    denotes F or Cl.

Particular preference is furthermore given to compounds of the formula Iin which R⁶ has one of the following meanings:

R⁷ preferably denotes H or A, in particular H.

Aryl preferably denotes phenyl, naphthyl or biphenyl, each of which isun-substituted or mono-, di- or trisubstituted by Hal, A, OH, OA, NH₂,NO₂, CN, COOH, COOA, CONH₂, NHCOA, NHCONH₂, NHSO₂A, CHO, COA, SO₂NH₂,SO₂A, —CH₂—COOH or —OCH₂—COOH.

Aryl preferably denotes phenyl, o-, m- or p-tolyl, o-, m- orp-ethylphenyl, o-, m- or p-propylphenyl, o-, m- or p-isopropylphenyl,o-, m- or p-tert-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-nitrophenyl, o-, m- or p-aminophenyl, o-,m- or p-(N-methylamino)phenyl, o-, m- orp-(N-methylaminocarbonyl)phenyl, o-, m- or p-acetamidophenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- orp-ethoxycarbonylphenyl, o-, m- or p-(N,N-dimethylamino)phenyl, o-, m- orp-(N,N-dimethylaminocarbonyl)phenyl, o-, m- or p-(N-ethylamino)phenyl,o-, m- or p-(N,N-diethylamino)phenyl, o-, m- or p-fluorophenyl, o-, m-or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-(methylsulfonamido)phenyl, o-, m- or p-(methylsulfonyl)phenyl,furthermore preferably 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dichlorophenyl,2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl, 2,4- or2,5-dinitrophenyl, 2,5- or 3,4-dimethoxyphenyl, 3-nitro-4-chlorophenyl,3-amino-4-chloro-, 2-amino-3-chloro-, 2-amino-4-chloro-,2-amino-5-chloro- or 2-amino-6-chlorophenyl,2-nitro-4-N,N-dimethylamino- or 3-nitro-4-N,N-dimethylaminophenyl,2,3-diaminophenyl, 2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or3,4,5-trichlorophenyl, 2,4,6-trimethoxyphenyl,2-hydroxy-3,5-dichlorophenyl, p-iodophenyl, 3,6-dichloro-4-aminophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl, 3-chloro-4-acetamidophenyl,3-fluoro-4-methoxyphenyl, 3-amino-6-methylphenyl,3-chloro-4-acetamidophenyl or 2,5-dimethyl-4-chlorophenyl.

Heteroaryl preferably denotes a mono- or bicyclic aromatic heterocyclehaving one or more N, O and/or S atoms which is unsubstituted or mono-,di- or trisubstituted by Hal, A, NO₂, NHA, NA₂, OA, COOA or CN.Heteroaryl particularly preferably denotes a monocyclic saturated oraromatic heterocycle having one N, S or O atom, which may beunsubstituted or mono-, di- or trisubstituted by Hal, A, NHA, NA₂, NO₂,COOA or benzyl.

Irrespective of further substitutions, unsubstituted heteroaryl denotes,for example, 2- or 3-furyl, 2- or 3-thienyl, 1-, 2- or 3-pyrrolyl, 1-,2,4- or 5-imidazolyl, 1-, 3-, 4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl,3-, 4- or 5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl,2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably1,2,3-triazol-1-, -4- or -5-yl, 1,2,4-triazol-1-, -3- or 5-yl, 1- or5-tetrazolyl, 1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or -5-yl,1,2,3-thiadiazol-4- or -5-yl, 3- or 4-pyridazinyl, pyrazinyl, 1-, 2-,3-, 4-, 5-, 6- or 7-indolyl, 4- or 5-isoindolyl, 1-, 2-, 4- or5-benzimidazolyl, 1-, 3-, 4-, 5-, 6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6-or 7-benzoxazolyl, 3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl, 4-, 5-, 6- or7-benz-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-,4-, 5-, 6-, 7- or 8-isoquinolyl, 3-, 4-, 5-, 6-, 7- or 8-cinnolinyl, 2-,4-, 5-, 6-, 7- or 8-quinazolinyl, 5- or 6-quinoxalinyl, 2-, 3-, 5-, 6-,7- or 8-2H-benzo-1,4-oxazinyl, furthermore preferably1,3-benzodioxol-5-yl, 1,4-benzodioxan-6-yl, 2,1,3-benzothiadiazol-4- or-5-yl or 2,1,3-benzoxadiazol-5-yl.

Hal preferably denotes F, Cl or Br, but also 1, particularly preferablyF or Cl.

Throughout the invention, all radicals which occur more than once may beidentical or different, i.e. are independent of one another.

The compounds of the formula I and also the starting materials for theirpreparation are, in addition, prepared by methods known per se, asdescribed in the literature (for example in the standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), to be precise underreaction conditions which are known and suitable for the said reactions.Use may also be made here of variants known per se which are notmentioned here in greater detail.

If desired, the starting materials may also be formed in situ so thatthey are not isolated from the reaction mixture, but instead areimmediately converted further into the compounds of the formula I.

The reaction is generally carried out in an inert solvent, preferably inthe presence of a protonic acid or Lewis acid, such as TFA, HFIP,bismuth(III) salts, ytterbium(III) salts or CAN. Depending on theconditions used, the reaction time is between a few minutes and 14 days,the reaction temperature is between about 0° and 180°, normally between0° and 100°, particularly preferably between 15° and 35° C.

Suitable inert solvents are, for example, hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, carbon tetrachloride,chloroform or dichloromethane; nitriles, such as acetonitrile; carbondisulfide; carboxylic acids, such as formic acid or acetic acid; nitrocompounds, such as nitromethane or nitrobenzene, or mixtures of the saidsolvents.

Compounds of the formula I in which R⁷ has a meaning other than H arepreferably prepared by alkylation or acylation from the compounds of theformula I in which R⁷ denotes H.

If desired, a functionally modified amino and/or hydroxyl group in acompound of the formula I can be liberated by solvolysis orhydrogenolysis by conventional methods. This can be carried out, forexample, using NaOH or KOH in water, water/THF or water/dioxane attemperatures between 0 and 100°.

The reduction of an ester to the aldehyde or alcohol or the reduction ofa nitrile to the aldehyde or amine is carried out by methods as areknown to the person skilled in the art and are described in standardworks of organic chemistry.

The invention furthermore relates to medicaments comprising at least onecompound of the formula I and/or pharmaceutically usable derivatives,solvates and stereoisomers thereof, including mixtures thereof in allratios, and optionally excipients and/or adjuvants.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. Such a unit can comprise, for example, 0.5 mg to 1 g,preferably 1 mg to 700 mg, particularly preferably 5 mg to 100 mg, of acompound according to the invention, depending on the condition treated,the method of administration and the age, weight and condition of thepatient, or pharmaceutical formulations can be administered in the formof dosage units which comprise a predetermined amount of activeingredient per dosage unit. Preferred dosage unit formulations are thosewhich comprise a daily dose or part-dose, as indicated above, or acorresponding fraction thereof of an active ingredient. Furthermore,pharmaceutical formulations of this type can be prepared using a processwhich is generally known in the pharmaceutical art.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

A therapeutically effective amount of a compound of the formula Idepends on a number of factors, including, for example, the age andweight of the animal, the precise condition which requires treatment,and its severity, the nature of the formulation and the method ofadministration, and is ultimately determined by the treating doctor orvet. However, an effective amount of a compound according to theinvention for the treatment of neoplastic growth, for example colon orbreast carcinoma, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The invention also relates to a process for the manufacture ofenantiomerically enriched or pure compounds of formula IA which arepreferred compounds of formula I and which can serve as intermediates inthe process for the manufacture of the enantiomerically enriched or purecompounds of formula I that differ from the compounds of formula IA:

whereinR¹, R², R³ and R⁶ are as defined aboveandR⁴, R⁵ are independenly of one another T-(CH₂)_(p)—R¹, together also—(CH₂)₅—, —(CH₂), —X—(CH₂)_(n)— or —(CH₂)_(n)-Z-(CH₂)_(n)—,wherein

-   T is —SO₂—, —CO—, —CONR¹—, —COO—, —CS—, —CSNR¹—, —COS—, —CSO—, —CSS    or a single bond,-   P is 0, 1, 2, 3, 4 or 5, preferably 1 or 2.-   n is as defined above.-   R¹ is preferably A, Cycloalkyl, —C(CH₃)₃, —CF₃, —SF₅, OCF₃, Hal,    —(CY₂), —CF₃, CN. Especially preferred is CF₃.

In especially preferred compounds of formula I and IA,

-   R² is preferably H or Hal, especially H.-   R³ is preferably H or Hal, especially H.-   R⁴, R⁵ is preferably H or A, CONH(CH₂)_(n)NA₂, SO₂NH(CH₂)_(n)NA₂ or    CO(CH₂)_(n)NA₂. Especially preferred are compounds of formula I and    also IA wherein R⁴ and R⁵ are simultaneously H or R⁴ is H and R⁵ is    A, preferably methyl.-   R⁶ is preferably aryl or hetaryl. Especially preferred is    unsubstitued or substituted aryl, preferably phenyl.

Preferred compounds of formula IA are those of formula IA1:

wherein R¹, R², R³, R⁴, R⁵ and R⁶ have the meanings given above.

Especially preferred are compounds of formula IB

wherein R⁴ and R⁵ are as defined above.

Preferred compounds of formula IB are those of formula IB1:

wherein R⁴ and R⁵ have the meaning given above.

The intermediates for the inventive manufacturing process, such ascompound IA, wherein R⁴ and R⁵ are H or A can also be obtained accordingto WO 2005/063735, especially by reaction of a compound Aa

with a compound Ba

and a compound C

preferably in the presence of a protonic acid or Lewis acid, such as,for example, trifluoroacetic acid, hexafluoroisopropanol, bismuth(III)chloride, ytterbium(III) triflate, scandium(III) triflate or cerium(IV)ammonium nitrate.

Surprisingly, it has been found that a racemic or non enantiomericallypure compound of formula IA, and especially a compound of formula IA,wherein R⁴ and R⁵ are both H, are forming complexes withenantiomerically pure tartraic acid derivatives, preferably benzoyltartraic acid and especially (2R,3R)-(−)-Di-O-benzoyl tartaric acid,which crystallize with high enantiomeric purity.

After separation of the crystalline phase from a suitable solvent, theenantiomerically further enriched or pure compound of formula IA can beobtained from the complex by reaction with a base, such as alkalihydroxide, preferably sodium hydroxide. The enantiomerically enriched orpure compounds of formula I are then obtained by standard synthesisstarting from the enriched or pure compounds of formula IA.

Thus, the invention relates to a process for the manufacture ofenantiomerically enriched or pure compounds of formula I, comprising thefollowing steps:

a) a racemic or non enantiomerically pure compound of formula IA isreacted with a enantiomerically pure tartraic acid derivative in asuitable solvent, preferably anorganic solvent, such that a crystallinecomplex is formedb) the complex formed in step a) is isolated and treated with a base andoptionallyc) the enantiomerically further enriched or pure compound of formula IAis transformed into the further compounds of formula I by standardprocedures, that transform the primary amino-group.

Standard procedures as defined under c) are e.g. alkylation, amidation,acylation hydroxylation. Preferably, a standard procedure is thereaction with carbonyldiimidazole and an amine such asN,N-Diethylethylenediamine.

In a preferred embodiment of the invention, a racemic or nonenantiomerically pure compound of formula IA, wherein R⁴ and R⁵ are bothH, or wherein R⁴ is H and R⁵ is alkyl, preferably methyl, is suspendedor dissolved in an organic solvent, such as an alcohol, preferablyethanol at temperatures between 20 and 120° C., preferably between 40and 90° C. and especially preferred at the boiling point of the solventat normal pressure.

Upon additon of the tartraic acid the solution is allowed to cool toabout room temperature and to stand for a period of a few hours to a fewdays, preferably about 1 to about 24 hous, especially about 8 to about20 hours. The crystals are separated and treated with sodium hydroxideto obtain the free base of formula IA.

In an especially preferred embodiment of the present invention, theenantiomerically enriched or pure compound II

(1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea)is obtained by the inventive process.

The term enantiomerically enriched or pure preferably refers to anenantiomeric purity of above 60%, such as about 80% to about 100%.Especially the term refers to an enantiomeric purity of higher thanabout 98%.

In the most preferred embodiment the present invention relates to theuse of a crystalline form of a compound of formula II and its use, forthe treatment of proliferative diseases such as cancer, pharmaceuticalcompositions containing the crystalline form and processes for itspreparation.

The compound of formula II as well as therapeutically acceptable saltsthereof, are described in WO 2005/063735.

The compound of formula II is therapeutically active and especiallyuseful in the treatment of proliferative diseases.

It has surprisingly been found that the compound of formula II isespecially stable in its basic, i.e. non-salt, form and can exist inmore than one crystalline form, such as A1, A2 and A3 preferably A1.Another object of the present invention is to provide a process for thepreparation of form A1 and A2 and A3, substantially free from otherforms of the compound of formula II, such as the amorphous form. X-raypowder diffraction (XRPD) is used as a method of differentiating formA1, A2 and A3 from each other and the non-crystalline or amorphous formof the compound of formula II. Additionally, it is an object of thepresent invention to provide pharmaceutical formulations comprising acompound of formula I in form A1 or A2 or A3, preferably A1.

Form A1 is a crystalline form which surprisingly exhibits advantageousproperties, such as being well-defined, being thermodynamically morestable and less hygroscopic than form A2, A3 and the amorphous form,especially at room temperature. Form A1 also shows a better chemicalstability, i.e. proviedes a longer shelf-life based on improved, thermalstability and light stability.

Form A2 and A3 can under certain conditions, completely or partly, beconverted into form A1. Form A1 is characterized in beingthermodynamically more stable than form A2 and A3.

Form A1 is further characterized as being essentially non-hygroscopic.

Form A1 can be distinguished from form A2, A3 and the amorphous form,using X-ray powder diffraction.

Characterization of form A1, form A2 and A3 can be performed accordingto standard methods which can be found in e.g. Bunn, C. W. (1948),Chemical Crystallography, Clarendon Press, London; or Klug, H. P.&Alexander, L. E. (1974), X-Ray Diffraction Procedures, John Wiley andSons, New York.

Form A1, according to the present invention, is characterized inproviding an X-ray powder diffraction pattern, exhibiting substantiallythe parameters given in FIG. 1.

According to the invention there is further provided a process for thepreparation of form A1, A2 and A3.

Form A1 may be prepared by crystallisation or recrystallizing thecompound of formula II of any form, or mixtures of any forms, in anappropriate solvent, such as for instance acetone/water or preferablyacetonitril or acetonitril/water, at around room temperature or elevatedtemperature and for a prolonged time period. Examples of prolonged timeperiods include, but are not limited to, a few hours, such as 2 hours,up to several weeks. Suitable solvents are, 2-propanol, acetonitrile,tetrahydrofurane, toluol, chloroform, formamide, 2-butanone or pyridine.Acetonitrile is most preferred. Further suitable solvents aresupercritical fluids and their modifies. Such solvents are e.g. carbondioxide, ethylene, propane, butane, dinitrogen oxide (N₂O). Suitablemodifies are ethanol, methanol or ethyl acetate. Other suitable solventsare consisting of larger molecules, such as transcutol, ethylenglycol,propylenglycol, solutol, capryol PGMC, Capryol 90, long chain aliphatichydrocarbons, e.g. hexane, octane, decane and long chain alcohols, suchas hexanols, octanols, decanols and their esters.

Form A1 may be prepared by suspending the compound of formula II of anyform, or mixtures of any forms, in the above solvents and preferablyacetonitrile at around room temperature or elevated temperature and fora prolonged time period. Examples of prolonged time periods include, butare not limited to, a few hours, such as 2 hours, up to several weeks.It may also be obtained by dissolving or suspending the compound offormula II of any form, or mixtures of any forms in the pure organicsolvent, preferably acetone, at the addition of an anti-solvent, such aswater.

Form A2 may be prepared by recrystallizing or suspending the compound offormula II of any form, preferably of A1, or mixtures of any forms, inn-heptane, at around room temperature or elevated temperature and for aprolonged time period. Examples of prolonged time periods include, butare not limited to, a few hours, such as 2 hours, up to several weeks.Form A2 is then obtained by evaporation of the solvent.

Form A3 may be prepared by dispensing the compound of formula II of anyform, preferably form A1, in n-heptane followed by stirring at roomtemperature for 1 to 20 days, preferably 1 to 10 days. Especiallypreferred are 1 to 5 days. A3 is then isolated by filtration and dryingin vacuo.

Form A1 obtained according to the present invention is substantiallyfree from other crystal and non crystalline, i.e. compounds forms of,such as Form A2 or A3. Substantially free from other forms shall beunderstood to mean that form A1 contains less than 10%, preferably lessthan 5%, of any other forms, e.g. form A2 and/or A3.

Form A2 obtained according to the present invention is substantiallyfree from other crystal and non crystalline, i.e. compounds forms of,such as Form A1. Substantially free from other forms shall be understoodto mean that form A2 contains less than 10%, preferably less than 5%, ofany other forms, e.g. form A1.

The present invention also relates to mixtures comprising form A1 inmixture with other solid forms of the compound of formula II. Suchmixtures comprise preferably more than 50% by weight of form A1. Otherembodiments include for instance mixtures containing a detectable amountof form A, 1%, 2%, 5%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%,98% or 99% (by weight), of form A1.

Examples of other solid forms of include, but are not limited to, formA2, A3 and an amorphous form. The amorphous form was found afterrecrystallization from DMF (dimethylformamide), DMSO, acetic acid andaqueous solutions at pH O-pH 6.

A detectable amount of form A1, A2 and A3 is an amount that can bedetected using conventional techniques, such as FT-IR, Ramanspectroscopy, XRPD and the like.

The expression chemical stability includes, but is not limited to,thermal stability and light stability.

The polymorphic forms of the invention, i.e. form A1, A2 and A3,prepared according to the present invention are analyzed, characterizedand differentiated from each other and the amorphous form by X-raypowder diffraction, a technique which is known per se. Another suitabletechnique to analyze, characterize and differentiate the individualforms is by Raman or IR spectroscopy.

The compounds of formula II also form stable solvates with varioussolvents. The individual solvates are another object of the presentinvention. The solvates are obtained by crystallization in therespective solvent, without addition of anti-solvent such as water.Preferred solvents for the manufacture of the solvates of the presentinvention are methyl tert-butylether (MTBE), acetone and ethylacetate.

Further preferred solvents for the manfucature of the novel solvates areethanol, 1-propanol, 1-butanol and isobutylmethylketone (IBMK). Othersolvates are obtained by use of the following solvents: Anisole,2-butanole, butyl acetate, cumene, ethyl ether, ethyl formiate, formicacid, isobutyl acetate, isopropyl acetate, methyl acetate,3-methyl-1-butanol, methyl ethylketone, pentane, 1-pentanole,2-pentanole, propyl acetate.

Any suitable route of administration may be employed for providing thepatient with an effective dosage of form A1, A2 or A3 according to theinvention. For example, peroral or parenteral formulations and the likemay be employed. Dosage forms include capsules, tablets, dispersions,suspensions and the like, e.g. enteric-coated capsules and/or tablets,capsules and/or tablets containing enteric-coated pellets of. In alldosage forms, the compounds of the formula II in form A1, A2 and A3 canbe admixtured with other suitable constituents.

According to the invention, there is further provided a pharmaceuticalcomposition comprising form A1, A2, or A3 preferably A1, as activeingredient, in association with a pharmaceutically acceptable carrier,diluent or excipient and optionally other therapeutic ingredients.Compositions comprising other therapeutic ingredients are especially ofinterest in the treatment of proliferative diseases, such as cancer. Theinvention also provides the use of form A1, A2 or A3 preferably A1 inthe manufacture of a medicament for use in the treatment ofproliferative diseases, such as cancer and related disorders andconditions and a method of treating the diseases, disorders orconditions which method comprises administering to a subject sufferingfrom said condition a therapeutically effective amount of form A1, A2 orA3.

The compositions of the invention include compositions suitable forperoral or parenteral administration. The compositions may beconveniently presented in unit dosage forms, and prepared by any methodsknown in the art of pharmacy.

In the practice of the invention, the most suitable route ofadministration as well as the magnitude of a therapeutic dose of formA1, A2 and A3 in any given case will depend on the nature and severityof the disease to be treated. The dose, and dose frequency, may alsovary according to the age, body weight, and response of the individualpatient.

The compound of the invention may be combined as the active component inintimate admixture with a pharmaceutical carrier according toconventional techniques, such as the oral formulations.

Combination therapies comprising the compound of formula II and otheractive pharmaceutical ingredients are disclosed in WO 2005/063735.

The respective combinations or mixtures of the compound of formula IIand other active pharmaceutical ingredients are also applicable to thecompound of formula II in form A1, A2 and A3.

The examples which follow will further illustrate the preparation of thecompound of the invention but are not intended to limit the scope of theinvention as defined hereinabove or as claimed below.

EXAMPLE 1 Synthesis of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

a.)

To a solution of 4-aminobenzotrifluoride (5.00 kg, 31.0 mol) in 10 Lacetonitrile was added under intensive cooling in an ice bathtrifluoroacetic acid (2.39 L, 31.0 mol) over a period of 20 min. In asecond vessel 3,4-dihydro-2H-pyran-2-methanol (3.61 kg, 31.0 mol) andbenzaldehyde (3.19 kg, 31 mol) were dissolved in 5 L acetonitrile andcooled to 10° C. To this solution the previously prepared TFA-salt of4-aminobenzotrifluoride was added over a period of 30 min keeping thetemperature below 15° C. The mixture was stirred for 14 h at 25° C.,cooled to 15° C. and the precipitate formed was filtered off and washedwith 2.5 L acetonitrile (3.36 kg yellow crystals).

To the crude product 12 L THF were added, heated to reflux and filteredat 50° C. 1.96 kg (5.39 kg, 17%) of yellow crystals identified as asingle trans-Isomer 1 were obtained. Analytics: m.p.: 282-283° C.

The filtrate was concentrated to a volume of 3 L, cooled to 4° C. andthe crystals formed overnight were filtered off (340 g of yellowcrystals, identified as 1:1 mixture of cis and trans isomers).

The filtrate was treated with 4 L of petrol ether, cooled to 4° C.overnight, the crystals formed were filtered off, washed with diethylether and dried. 524 g (1.44 mol, 5%) of greenish crystals found to be acis-Isomer were obtained.

b.)

Compound 1 (330 g, 0.91 mol) was suspended in 10 L of DCM. To thissuspension triethyl amine (208 mL, 1.50 mmol) and methanesulfonylchloride (101 mL, 1.30 mol), dissolved in 200 mL of DCM, were added at22° C. During the addition the temperature increased to 30° C. and themixture turned clear after 1 h at RT. It was stirred at RT overnight andthe solution was poured onto ice water. The organic layer was separatedand washed with water 3 times. It was dried over sodium sulfate,filtered and the solvent was evaporated. The crude product wasredissolved/suspended in hot ethanol (0.5 L), stirred for 2 h and cooledto 4° C. overnight. The precipitate was filtered off and dried. 383 g(0.87 mol, 96%) of a colorless solid 2 were obtained.

c.)

In an autoclave 3.00 g (6.80 mmol) mesylate 2 was dissolved in 30 mL ofmethanol. The reaction mixture was stirred and the autoclave cooled andflushed with ammonia gas. The gas inside the autoclave was removed byreduced pressure. The autoclave was again flushed with ammonia gas. Theammonia pressure was allowed to rise to 5 bar. The temperature wasbrought up to 100° C. and the reaction mixture was stirred overnight.During the reaction the product precipitated. The autoclave was cooleddown and decompressed. The reaction mixture was collected, 100 mLmethanol was added and cooled down to 0° C. The resulting crystals werecollected by filtration to afford 2.14 g (5.91 mmol, 87%) amine 3, whichwas directly used for the next step without further purification.

d.)

7.18 g (19.8 mmol) racemic amine 3 was suspended in 200 mL ethanol andheated to reflux. 3.55 g (9.9 mmol) (2R,3R)-(−)-Di-O-benzoyl tartaricacid and 20 mL ethanol were added and the solution heated to reflux. Thesolution was filtered and the filter washed with 30 mL ethanol. Thefiltrate was allowed to stand for about 18 h at room temperature. Duringthat time precipitation started. The crystals were collected byfiltration, washed with a little amount of cold ethanol and thenair-dried to give 3.53 g (3.3 mmol, 33%) of the diamine tartaric acidsalt. Analytics: m.p.: 169-171° C.; [α]_(D) ²⁰=−101.6°(MeOH, c=0.51).

11.9 g (11.0 mmol) diamine tartaric acid salt was suspended in 200 mL 2N NaOH. After 15 min the reaction mixture was extracted with 750 mLethyl acetate. The organic layer was washed with brine, dried withNa₂SO₄ and the solvents removed under reduced pressure to yield 7.82 g(21.6 mmol, 98%) of the enantiomerically pure amine 4.

e.)

Compound 4 (168 g, 0.46 mol) was dissolved in DCM (2 L) and thecarbonyldiimidazole (81.1 g, 0.50 mol) was added in small portions overa period of 10 min at RT. The mixture was stirred for 2 h at RT. The TLCshowed complete consumption of the starting material.

Then, N,N-Diethylethylenediamine (110 mL, 1.01 mol) was added over aperiod of 10 min at which the temperature increased to 27° C. Themixture was stirred at RT for 15 h and poured onto ice water (3 L). ThepH was titrated to pH 8 by adding diluted HCl solution, the organicphase was separated and washed with water (2 L) twice. The solution wasdried over sodium sulfate, filtered and the solvent was evaporated underreduced pressure. The remainder was diluted with diethyl ether, theprecipitate was filtered off, washed with diethyl ether and dried invacuo (188 g (0.40 mol, 85%) of colorless crystals identified as1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea.

The filtrate was cooled to 4° C. overnight and additional 18 g (0.04 g,8%) of the desired product 5 were filtered off and dried in vacuo.

The combined fractions were redissolved in acetone (1 L), warmed to 40°C. and water (3 L) was added slowly. The mixture was cooled to 4° C. for3 h, the precipitate formed was filtered off and dried for 3 d at 80° C.under reduced pressure. 192 g (0.40 mol, 87%) of compound 5 as acolorless solid were obtained. Analytics: m.p.: 123° C., [α]_(D)²⁰=−85.6°(MeOH, c=1.07).

EXAMPLE 2

Compound 1 (3.9 g, 8.83 mmol) was added into a methylamine solution (40mL, 33% solution in ethanol) and the reaction mixture was stirredovernight at 100° C. For completion of the reaction additionalmethylamine (20 mL, 33% solution in ethanol) was added and the reactionmixture was stirred overnight at 100° C. The reaction mixture was cooleddown to room temperature. During the cooling precipitation occurred. Theresulting crystals were collected by filtration and dried at 35° C. in avacuum drying oven. Yield: 1.17 g clear crystals. The remaining residuesolution was concentrated under reduced pressure and treated witht-butyl methyl ether. The resulting crystals were collected byfiltration and dried at 35° C. in a vacuum drying oven. Yield: 1.6 gclear crystals. The material from both crystallization was combined,resulting in 2.77 g (7.35 mmol, 83% yield) compound rac-2.

Compound rac-2 (0.93 g, 2.47 mmol) was dissolved in 15 mL ethanol andheated to reflux. 0.45 g (1.24 mmol) (2R,3R)-(−)-Di-O-benzoyl tartaricacid and 25 mL ethanol were added and the solution heated to reflux. Thesolution was filtered and the filter washed with 5 mL hot ethanol. Thefiltrate was allowed to stand for about 18 h at room temperature. Duringthat time precipitation started. The crystals were collected byfiltration, washed with a little amount of cold ethanol and thenair-dried to give compound (−)-2 (0.42 g, 0.38 mmol) as diamine tartaricacid salt. Analytics: m.p. 200-203° C., α_(D)=−105.8° (methanol).

A sample of the crystals was treated with 1 N NaOH, extracted with ethylacetate and the solvent removed under reduced pressure. The opticalpurity of resulting compound (−)-2 was determined >98% by chiral HPLC.

EXAMPLE 3

Form A1 (stable polymorph) of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

I) Seeding Crystals

Under gentle warming the compound of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(1 g) was dissolved in 2-propanole (50 mL). All solvents were removedunder reduced pressure. Under gentle warming a part of the resultingresidue (0.5 g) was dissolved in acetone (4.5 mL). Water (4.0 mL) wasadded until the crystallization started. Additional water (2 mL) wasadded and the mixture was allowed to stand for 18 h at 0° C. (ice-bath).The resulting crystals were collected by filtration, washed with coldwater and dried (80° C., 0.3 torr) to receive clear crystals (0.45 g) of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea.The crystals were used as seeding crystals (see section II).

II) Crystallization

Under gentle warming the compound of formula I (271.6 g) was dissolvedin acetone (2 L). All solvents were removed under reduced pressure. Theremaining residue (261 g) was dissolved in warm acetone (1 L). Water (3L) was added slowly. When approx. 2.6 L water was added the beforehandclear solution turned misty. Seeding crystals (see section 1) were addedand the mixture was allowed to stand for 3 h at 0° C. (ice-bath). Theresulting crystals were collected by filtration and washed with coldwater. The obtained crystals were dried for 3 d (80° C., 1 torr) to giveclear crystals (243 g) of the1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureaas form A1.

XRPD Diffractogram (FIG. 1)

No., d/Å, 2θ±0.1, I/Io1, 13.90, 6.35, 100; 2, 11.32, 7.81, 52; 3, 9.74, 9.07, 36; 4, 8.51,10.38, 27; 5, 6.41, 13.80, 37; 6, 5.40, 16.39, 58; 7, 4.86, 18.22, 94;8, 4.78, 18.55, 49; 9, 4.35, 20.39, 55; 10, 4.30, 20.65, 54

Raman Spectrum (FIG. 4)

wavenumber/cm⁻¹3059±1.5 m, 2948±1.5 m, 2922±1.5 m, 2897±1.5 m, 2867±1.5 m, 2783±1.5 m,1663±1.5 w, 1627±1.5 s, 1606±1.5 m, 1587±1.5 w, 1457±1.5 m, 1374±1.5 w,1346±1.5 w, 1330±1.5 m, 1320±1.5 w, 1264±1.5 w, 1204±1.5 w, 1190±1.5 w,1159±1.5 w, 1132±1.5 w, 1083±1.5 w, 1064±1.5 m, 1029±1.5 m, 1002±1.5 m,955±1.5 w, 925±1.5 w, 881±1.5 m, 831±1.5 m, 797±1.5 m, 761±1.5 m,746±1.5 m, 674±1.5 m, 621±1.5 w, 507±1.5 w, 456±1.5 w,

IR Spectrum (FIG. 7)

wavenumber/cm⁻¹3452±1.5 w, 3301±1.5 m, 3063±1.5 w, 3033±1.5 w, 2945±1.5 m, 2923±1.5 w,2896±1.5 w, 2863±1.5 w, 2830±1.5 w, 1660±1.5 m, 1627±1.5 s, 1524±1.5 w,1496±1.5 w, 1455±1.5 m, 1320±1.5 s, 1262±1.5 m, 1202±1.5 w, 1189±1.5 m,1161±1.5 m, 1129±1.5 m, 1104±1.5 s, 1070±1.5 m, 1064±1.5 w, 1029±1.5 m,952±1.5 w, 9411±1.5 w, 904±1.5 w, 880±1.5 w, 867±1.5 w, 833±1.5 m,827±1.5 m, 760±1.5 m, 707±1.5 m, 672±1.5 w, 644±1.5 w, 635±1.5 m,505±1.5 w, 455±1.5 w

EXAMPLE 4 Form A2 (Metastable Polymorph) of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea(50 mg, 0.105 mmol) form A1 was dispensed in n-heptane (200 mL) and theslurry stirred at room temperature for 5 days. The slurry wastransferred into a petri dish and dried in a cabinet drier in air at 40°C. for 1 day. The recrystallized substance was identified as1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the polymorphic form A2.

XRPD Diffractogram (FIG. 2)

No., d/Å, 2θ±0.1, I/Io1, 23.71, 3.7, 100; 2, 19.44, 4.5, 54; 3, 15.41, 5.7, 37; 4, 12.00, 7.4,27; 5, 5.96, 14.8, 25; 6, 5.36, 16.5, 28; 7, 4.65, 19.1, 93; 8, 4.56,19.5, 27; 9, 4.25, 20.9, 41; 10, 4.20, 21.1, 27

Raman Spectrum (FIG. 5)

wavenumber/cm⁻¹3060±1.5 m, 2946±1.5 m, 2865±1.5 w, 2779±1.5 w, 1624±1.5 m, 1606±1.5 m,1587±1.5 m, 1443±1.5 m, 1328±1.5 m, 1261±1.5 w, 1179±1.5 w, 1157±1.5 w,1063±1.5 w, 1030±1.5 m, 1002±1.5 m, 896±1.5 m, 831±1.5 w, 800±1.5 w,764±1.5 m, 745±1.5 w, 674±1.5 w, 621±1.5 w, 504±1.5 w

IR Spectrum (FIG. 8)

wavenumber/cm⁻¹3451±1.5 w, 3306±1.5 m, 3064±1.5 w, 3032±1.5 w, 2943±1.5 m, 2924±1.5 w,2896±1.5 w, 2861±1.5 w, 2828±1.5 w, 1658±1.5 m, 1626±1.5 s, 1570±1.5 m,1524±1.5 m, 1496±1.5 w, 1455±1.5 m, 1320±1.5 s, 1261±1.5 m, 1202±1.5 w,1188±1.5 m, 1160±1.5 m, 1131±1.5 m, 1104±1.5 s, 1071±1.5 m, 1064±1.5 m,1029±1.5 m, 954±1.5 w, 941±1.5 w, 904±1.5 w, 880±1.5 w, 869±1.5 w,833±1.5 m, 761±1.5 m, 706±1.5 m, 672±1.5 w, 645±1.5 w, 635±1.5 m,503±1.5 w, 455±1.5 w.

EXAMPLE 5 Form A3 (Metastable Polymorph) of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea

(100 mg, 0.210 mmol) form A1 was dispensed in n-heptane (35 mL) and theslurry stirred at room temperature for 5 days. The precipitate wasfiltered off using a paper filter and immediately dried in vacuo. Thesubstance was identified as1-(2-Dimethylamino-ethyl)-3-((2R,4aS,R5,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the polymorphic form A3.

XRPD Diffractogram

No., d/Å, 2θ±0.1, I/Io1, 23.81, 3.7, 100; 2, 19.74, 4.5, 68; 3, 15.56, 5.7, 55; 4, 11.96, 7.4,45; 5, 9.99, 8.8, 30; 6, 9.22, 9.6, 28; 7, 8.57, 10.3, 25; 8, 7.87,11.2, 26; 9, 7.41, 11.9, 30; 10, 6.41, 13.8, 26; 11, 5.96, 14.9, 34; 12,5.80, 15.3, 28; 13, 5.35, 16.6, 35; 14, 5.21, 17.0, 24; 15, 4.95, 17.9,28; 16, 4.81, 18.4, 32; 17, 4.64, 19.1, 75; 18, 4.43, 20.0, 25; 19,4.24, 21.0, 43; 20, 4.15, 21.4, 30; 21, 3.95, 22.5, 15; 22, 3.75, 23.7,20; 23, 3.65, 24.3, 19; 24, 3.45, 25.8, 11; 25, 3.38, 26.4, 15; 26,3.26, 27.4, 11; 27, 3.03, 29.4, 9; 28, 2.87, 31.2, 7; 29, 2.74, 32.6, 8;30, 2.44, 36.9, 5; 31, 2.32, 38.8, 6; 32, 2.18, 41.3, 6; 33, 2.13, 42.4,6; 34, 3.00, 29.8, 9; 35, 3.60, 24.7, 17; 36, 7.31, 12.1, 29; 37, 5.04,17.6, 21; 38, 3.86, 23.0, 14; 39, 4.32, 20.6, 21.

Ramen Spectrum (FIG. 6) Wavenumber/cm⁻¹

3066±1.5 m, 3060±1.5 s, 2946±1.5 s, 2863±1.5 m, 2779±1.5 w, 1624±1.5 s,1606±1.5 m, 1444±1.5 m, 1328±1.5 m, 1261±1.5 m, 1179±1.5 m, 1157±1.5 m,1063±1.5 w, 1030±1.5 m, 1002±1.5 s, 896±1.5 m, 831±1.5 m, 800±1.5 m,764±1.5 m, 674±1.5 m, 621±1.5 m, 504±1.5 m

IR Spectrum (FIG. 9) Wavenumber/cm⁻¹

3306±1.5 m, 2943±1.5 m, 2861±11.5 m, 1658±11.5 m, 1626±11.5 s, 1570±1.5m, 1525±1.5 m, 1455±1.5 m, 1320±1.5 s, 1261±1.5 m, 1188±1.5 m, 1160±1.5m, 1131±1.5 m, 1104±1.5 m, 1064±1.5 m, 1029±1.5 m, 833±1.5 m, 761±1.5 m,706±1.5 m, 635±1.5 m

1. Process for the manufacture of enantiomerically enriched or purecompounds of formula I

wherein R¹, R², R³ independently of one another is H, A, Aryl,Heteroaryl, Hal, —(CY₂)_(n)—SA, —(CY₂)_(n)—SCF₃, —(CY₂), —SCN,—(CY₂)_(n)—CF₃, —(CY₂), —OCF₃, R, Cycloalkyl, —SCH₃, —SCN, —CF₃, —OCF₃,—OA, —(CY₂), —OH, —(CY₂), —CO₂R, —(CY₂), —CN, —(CY₂)_(n)—Hal,—(CY₂)_(n)—NR₂, (CY₂)_(n)—OA, (CY₂)_(n)—OCOA, —SCF₃, (CY₂), —CONR₂,—(CY₂), —NHCOA, —(CY₂), —NHSO₂A, SF₅, Si(CH₃)₃, CO—(CY₂)_(n)—CH₃,—(CY₂), —N-Pyrolidon, (CH₂)_(n)NRCOOR, NRCOOR, NCO, (CH₂)_(n)COOR,NCOOR, (CH₂)_(n)OH, NR(CH₂)_(n)NR₂, C(OH)R₂, NR(CH₂)_(n)OR, NCOR,(CH₂)_(n)Aryl, (CH₂)_(n)Heteroaryl, (CH₂)_(n)R, (CH₂)_(n)X(CH₂)_(n)Aryl,(CH₂)_(n)X(CH₂)_(n)Heteroaryl, (CH₂)_(n)CONR₂, XCONR(CH₂)_(n)NR₂,N[(CH₂)_(n)XCOOR]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)XR]CO(CH₂)_(n)Aryl,N[(CH₂)_(n)XR]CO(CH₂)_(n)XAryl, N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Aryl,N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Aryl,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRAryl, N[(CH₂)_(n)NR₂]SO₂(CH₂)_(n)Aryl,N[(CH₂)_(n)XR]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)XR]CO(CH₂)_(n)XHeteroaryl,N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRHeteroaryl and wherein, R¹ and R³ togetheralso may be —N—C(CF₃)═N—, —N—CR═N— or —N—N═N— and wherein non-adjacentgroups CY₂ can be replaced by X Y is H, A, Hal, OR, E-R¹, E is —NR¹SO₂—,—NR¹CO—, NR¹CONR—, —NR¹COO—, —NR¹CS—, —NR¹CSNR¹—, —NR¹COS—, NR¹CSO—,—NR¹CSS or —NR¹— A is Alkyl or Cycloalkyl, wherein one or more H-atomscan be replaced by Hal, Hal is F, Cl, Br or I R is H or A, in the caseof geminal groups R together also —(CH₂)₅—, —(CH₂)₄— or —(CH₂),—X—(CH₂)_(n), or —(CH₂)_(n)-Z-(CH₂)_(n), X is O, S or NR¹, Q isCH₂-E-(CH₂)_(p)R¹, Z is CH₂, X, CHCONH₂, CH(CH₂)_(n)NR¹COOR¹,CHNR¹COOR¹, NCHO, CHCON(R¹)₂, CH(CH₂)_(n)COOR¹, NCOOR¹, CH(CH₂)_(n)OH,N(CH₂)_(n)OH, CHNH₂, CH(CH₂)_(n)NR₂, CH(CH₂)_(n)NR₁₂, C(OH)R¹, CHNCOR¹,NCOR¹, N(CH₂)_(n)Aryl, N(CH₂)_(n)Heteroaryl, CHR¹, NR¹, CH(CH₂)_(n)Aryl,CH(CH₂)_(n)Heteroaryl, CH(CH₂)_(n)R¹, N(CH₂)_(n)COOR¹,CH(CH₂)_(n)X(CH₂)_(n)Aryl, CH(CH₂)_(n)X(CH₂)_(n)Heteroaryl,N(CH₂)_(n)CON(R¹)₂, NSO₂R¹, CHSO₂N(R¹)₂, XCONR(CH₂)_(n)N(R¹)₂,NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)XAryl, NSO₂(CH₂)_(n)Aryl,NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)NR¹Aryl, NCO(CH₂)_(n)Heteroaryl,NCO(CH₂)_(n)XHeteroaryl, NSO₂(CH₂)_(n)Heteroaryl,NCO(CH₂)_(n)NRIHeteroaryl, N(CH₂)_(n)NR₂CH, CHO(CH₂)_(n)N(R¹)₂,CHX(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n)NR₂, R⁶ is unsubstituted Aryl orHeteroaryl or Aryl or Heteroaryl which is substituted in at least oneposition by Hal, NO₂, CN, OR, A, —(CY₂), —OR, —OCOR, —(CY₂), —CO₂R,—(CY₂)_(n)—CN, —NCOR, —COR oder —(CY₂), —NR₂ or by Aryl or Heteroarylwhich also may be substituted by Hal, NO₂, CN, A, OR, OCOR, COR, NR₂,CF₃, OCF₃, OCH(CF₃)₂, R⁷ is (C═O)—R, (C═O)—NR₂, (C═O)—OR, H or A and nis 0, 1, 2, 3, 4, 5, 6 or 7 p is 0, 1, 2, 3, 4, or 5, preferred 1 or 2 sis 0, 1, 2, 3 or 4, particularly 0 as well as their pharmaceuticallyacceptable derivatives, solvates, tautomeres, salts and polymorphicforms comprising the following steps: a) a racemic or nonenantiomerically pure compound of formula IA

wherein R¹, R², R³ and R⁶ are as defined above and R⁴, R⁵ areindependenly of one another T-R¹ wherein T is —SO₂—, —CO—, —CONR¹—,—COO—, —CS—, —CSNR¹—, —COS—, —CSO—, —CSS or a single bond, is reactedwith an enantiomerically pure tartraic acid derivative, such that acrystalline complex is formed b) the complex formed in step a) isisolated and treated with a base and optionally c) the enantiomericallyfurther enriched or pure compound of formula IA is transformed into thefurther compounds of formula I.
 2. Process according to claim 1, whereinR⁴ and R⁵ of formula IA are both H.
 3. Process according to claim 1,wherein R⁴ is H and R⁵ is methyl.
 4. Process according to claim 1 forthe preparation of compounds of formula IB

wherein R⁴ and R⁵ are as defined in claims 2 and
 3. 5. Process accordingto claim 1, wherein the tartaric acid derivative is(2R,3R)-(−)-Di-O-benzoyl tartaric acid.
 6. Process according to claim 1,wherein1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureais obtained.
 7. The compound1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea.8. The compound1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline Form A1 having the following data: XRPD diffractogramNo., d/Å, 2θ±0.1, I/Io 1, 13.90, 6.35, 100; 2, 11.32, 7.81, 52; 3, 9.74,9.07, 36; 4, 8.51, 10.38, 27; 5, 6.41, 13.80, 37; 6, 5.40, 16.39, 58; 7,4.86, 18.22, 94; 8, 4.78, 18.55, 49; 9, 4.35, 20.39, 55; 10, 4.30,20.65, 54 Raman spectrum wavenumber/cm⁻¹ 3059±1.5 m, 2948±1.5 m,2922±1.5 m, 2897±1.5 m, 2867±1.5 m, 2783±1.5 m, 1663±1.5 w, 1627±1.5 s,1606±1.5 m, 1587±1.5 w, 1457±1.5 m, 1374±1.5 w, 1346±1.5 w, 1330±1.5 m,1320±1.5 w, 1264±1.5 w, 1204±1.5 w, 1190±1.5 w, 1159±1.5 w, 1132±1.5 w,1083±1.5 w, 1064±1.5 m, 1029±1.5 m, 1002±1.5 m, 955±1.5 w, 925±1.5 w,881±1.5 m, 831±1.5 m, 797±1.5 m, 761±1.5 m, 746±1.5 m, 674±1.5 m,621±1.5 w, 507±1.5 w, 456±1.5 w, IR spectrum wavenumber/cm⁻¹ 3452±1.5 w,3301±1.5 m, 3063±1.5 w, 3033±1.5 w, 2945±1.5 m, 2923±1.5 w, 2896±1.5 w,2863±1.5 w, 2830±1.5 w, 1660±1.5 m, 1627±1.5 s, 1524±1.5 w, 1496±1.5 w,1455±1.5 m, 1320±1.5 s, 1262±1.5 m, 1202±1.5 w, 1189±1.5 m, 1161±1.5 m,1129±1.5 m, 1104±1.5 s, 1070±1.5 m, 1064±1.5 w, 1029±1.5 m, 952±1.5 w,941±1.5 w, 904±1.5 w, 880±1.5 w, 867±1.5 w, 833±1.5 m, 827±1.5 m,760±1.5 m, 707±1.5 m, 672±1.5 w, 644±1.5 w, 635±1.5 m, 505±1.5 w,455±1.5 w.
 9. The compoundI-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline Form A2 having the following data: XRPD diffractogramNo., d/Å, 2θ±0.1, I/Io 1, 23.71, 3.7, 100; 2, 19.44, 4.5, 54; 3, 15.41,5.7, 37; 4, 12.00, 7.4, 27; 5, 5.96, 14.8, 25; 6, 5.36, 16.5, 28; 7,4.65, 19.1, 93; 8, 4.56, 19.5, 27; 9, 4.25, 20.9, 41; 10, 4.20, 21.1, 27Raman spectrum wavenumber/cm⁻¹ 3060±1.5 m, 2946±1.5 m, 2865±1.5 w,2779±1.5 w, 1624±1.5 m, 1606±1.5 m, 1587±1.5 m, 1443±1.5 m, 1328±1.5 m,1261±1.5 w, 1179±1.5 w, 1157±1.5 w, 1063±1.5 w, 1030±1.5 m, 1002±1.5 m,896±1.5 m, 831±1.5 w, 800±1.5 w, 764±1.5 m, 745±1.5 w, 674±1.5 w,621±1.5 w, 504±±1.5 w IR spectrum wavenumber/cm⁻¹ 3451±1.5 w, 3306±1.5m, 3064±1.5 w, 3032±1.5 w, 2943±1.5 m, 2924±1.5 w, 2896±1.5 w, 2861±1.5w, 2828±1.5 w, 1658±1.5 m, 1626±1.5 s, 1570±1.5 m, 1524±1.5 m, 1496±1.5w, 1455±1.5 m, 1320±1.5 s, 1261±1.5 m, 1202±1.5 w, 1188±1.5 m, 1160±1.5m, 1131±1.5 m, 1104±1.5 s, 1071±1.5 m, 1064±1.5 m, 1029±1.5 m, 954±1.5w, 941±1.5 w, 904±1.5 w, 880±1.5 w, 869±1.5 w, 833±1.5 m, 761±1.5 m,706±1.5 m, 672±1.5 w, 645±1.5 w, 635±1.5 m, 503±1.5 w, 455±1.5 w
 10. Thecompound1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline Form A3 having the following data: Raman spectrumWavenumber/cm⁻¹ 3066±1.5 m, 3060±1.5 s, 2946±1.5 s, 2863±1.5 m, 2779±1.5w, 1624±1.5 s, 1606±1.5 m, 1444±1.5 m, 1328±1.5 m, 1261±1.5 m, 1179±1.5m, 1157±1.5 m, 1063±1.5 w, 1030±1.5 m, 1002±1.5 s, 896±1.5 m, 831±1.5 m,800±1.5 m, 764±1.5 m, 674±1.5 m, 621±1.5 m, 504±1.5 m IR spectrumWavenumber/cm⁻¹ 3306±1.5 m, 2943±1.5 m, 2861±1.5 m, 1658±1.5 m, 1626±1.5s, 1570±1.5 m, 1525±1.5 m, 1455±1.5 m, 1320±1.5 s, 1261±1.5 m, 1188±1.5m, 1160±1.5 m, 1131±1.5 m, 1104±1.5 m, 1064±1.5 m, 1029±1.5 m, 833±1.5m, 761±1.5 m, 706±1.5 m, 635±1.5 m.
 11. A method for the treatment of adisease which can be influenced by the inhibition, regulation and/ormodulation of the mitotic motor protein Eg5, comprising administering toa patient an effective amount of the compound1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-urea.12. A method according to claim 11, wherein said compound is1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline form A1.
 13. A method according to claim 11, whereinsaid compound is Use of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline from A2.
 14. A method according to claim 11, whereinsaid compound is Use of1-(2-Dimethylamino-ethyl)-3-((2R,4aS,5R,10bS)-5-phenyl-9-trifluoromethyl-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinolin-2-ylmethyl)-ureain the crystalline from A3.
 15. (canceled)
 16. A method according toclaim 11, wherein said method is for the treatment and prophylaxis ofcancer diseases.
 17. A method according to claim 16, where the cancerdiseases are associated with a tumor from the group of tumours of thesquamous epithelium, of the bladder, of the stomach, of the kidneys, ofhead and neck, of the oesophagus, of the cervix, of the thyroid, of theintestine, of the liver, of the brain, of the prostate, of theurogenital tract, of the lymphatic system, of the stomach, of the larynxand/or of the lung.
 18. A method according to claim 17, where the tumouroriginates from the group monocytic leukaemia, lung adenocarcinoma,small-cell lung carcinomas, pancreatic cancer, glioblastomas and breastcarcinoma and colon carcinoma.
 19. A method according to claim 18, wherethe cancer disease to be treated is a tumour of the blood and immunesystem.
 20. A method according to claim 19, where the tumour originatesfrom the group acute myelotic leukaemia, chronic myelotic leukaemia,acute lymphatic leukaemia and/or chronic lymphatic leukaemia. 21.Enantiomerically enriched or pure compounds of formula IA or IB.

wherein R¹, R², R³ independently of one another is H, A, Aryl,Heteroaryl, Hal, —(CY₂)_(n)C SA, —(CY₂)_(n)—SCF₃, —(CY₂)_(n)—SCN,—(CY₂)_(n)—CF₃, —(CY₂)_(n)—OCF₃, R, Cycloalkyl, —SCH₃, —SCN, —CF₃,—OCF₃, —OA, —(CY₂)_(n)—OH, —(CY₂)_(n)—CO₂R, —(CY₂)_(n)—CN,—(CY₂)_(n)-Hal, —(CY₂)_(n)—NR₂, (CY₂)_(n)—OA, (CY₂)_(n)—OCOA, —SCF₃,(CY₂)_(n)—CONR₂, —(CY₂)_(n)—NHCOA, —(CY₂)_(n)—NHSO₂A, SF₅, Si(CH₃)₃,CO—(CY₂)_(n)—CH₃, —(CY₂)_(n)—N-Pyrolidon, (CH₂)_(n)NRCOOR, NRCOOR, NCO,(CH₂)_(n)COOR, NCOOR, (CH₂)_(n)OH, NR(CH₂)_(n)NR₂, C(OH)R₂,NR(CH₂)_(n)OR, NCOR, (CH₂)_(n)Aryl, (CH₂)_(n)Heteroaryl, (CH₂)_(n)R¹,(CH₂)_(n)X(CH₂)_(n)Aryl, (CH₂)_(n)X(CH₂)_(n)Heteroaryl, (CH₂)_(n)CONR₂,XCONR(CH₂)_(n)NR₂, N[(CH₂)_(n)XCOOR]CO(CH₂)_(n)Aryl,N[(CH₂)_(n)XR]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)XR]CO(CH₂)_(n)XAryl,N[(CH₂)_(n)XR]SO₂(CH₂)_(n)Aryl, N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)ArylN[(CH₂)_(n)NR₂]CO(CH₂)_(n)Aryl, N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRAryl,N[(CH₂)_(n)NR₂]SO₂(CH₂)_(n)Aryl, N[(CH₂)_(n)XR]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)XR]CO(CH₂)_(n)XHeteroaryl,N[(CH₂)_(n)XR]SO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NRCOOR]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)Heteroaryl,N[(CH₂)_(n)NR₂]CO(CH₂)_(n)NRHeteroaryl and wherein, R¹ and R³ togetheralso may be —N—C(CF₃)═N—, —N—CR═N— or —N—N═N— and wherein non-adjacentgroups CY₂ can be replaced by X Y is H, A, Hal, OR, E-R¹, E is —NR¹SO₂—,—NR¹CO—, NR¹CONR¹—, —NR¹COO—, —NR¹CS—, —NR¹CSNR¹—, —NR¹COS—, NR¹CSO—,—NR¹CSS or —NR¹— A is Alkyl or Cycloalkyl, wherein one or more H-atomscan be replaced by Hal, Hal is F, Cl, Br or I R is H or A, in the caseof geminal groups R together also —(CH₂)₅—, —(CH₂)₄— or—(CH₂)_(n)—X—(CH—), or —(CH₂)_(n)-Z-(CH₂)_(n), X is O, S or NR¹, Z isCH₂, X, CHCONH₂, CH(CH₂)_(n)NR¹COOR¹, CHNR¹COOR¹, NCHO, CHCON(R¹)₂,CH(CH₂)_(n)COOR¹, NCOOR¹, CH(CH₂)_(n)OH, N(CH₂)_(n)OH,CHNH₂CH(CH₂)_(n)NR¹ ₂, CH(CH₂)_(n)NR¹ ₂, C(OH)R¹, CHNCOR¹, NCOR¹,N(CH₂)_(n)Aryl, N(CH₂)_(n)Heteroaryl, CHR¹, NR¹, CH(CH₂)_(n)Aryl,CH(CH₂)_(n)Heteroaryl, CH(CH₂)_(n)R¹, N(CH₂)_(n)COOR¹,CH(CH₂)_(n)X(CH₂)_(n)Aryl, CH(CH₂)_(n)X(CH₂)_(n)Heteroaryl,N(CH₂)_(n)CON(R¹)₂, NSO₂ ¹R, CHSO₂N(R¹)₂, XCONR(CH₂)_(n)N(R¹)₂,NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)XAryl, NSO₂(CH₂)_(n)Aryl,NCO(CH₂)_(n)Aryl, NCO(CH₂)_(n)NR¹Aryl, NCO(CH₂)_(n)Heteroaryl,NCO(CH₂)_(n)Heteroaryl, NSO₂(CH₂)_(n)Heteroaryl,NCO(CH₂)_(n)NR¹Heteroaryl, N(CH₂)_(n)NR₂CH, CHO(CH—)_(n)N(R¹)₂,CHX(CH₂)_(n)N(R¹)₂, NCO(CH₂)_(n), NR₂, R⁶ is unsubstituted Aryl orHeteroaryl or Aryl or Heteroaryl which is substituted in at least oneposition by Hal, NO₂ CN, OR, A, —(CY₂)_(n)—OR, —OCOR, —(CY₂)_(n)—CO₂R,—(CY₂)_(n)—CN, —NCOR, —COR or —(CY₂)_(n)—NR₂ or by Aryl or Heteroarylwhich also may be substituted by Hal, NO₂, CN, A, OR, OCOR, COR, NR—,CF₃, OCF₃, OCH(CF₃)₂, n is 0, 1, 2, 3, 4, 5, 6 or 7 p is 0, 1, 2, 3, 4,or 5, preferred 1 or 2 s is 0, 1, 2, 3 or 4, particularly 0 R⁴, R⁵ areindependenly of one another T-R¹, and T is —SO₂—, —CO—, —CONR1—, —COO—,—CS—, —CSNR¹—, —COS—, —CSO—, —CSS or a single bond.